The new EU regulations will require much more documentation and perhaps some new evaluations from medical device manufacturers. An expert explains how to perform a gap analysis and begin preparing now for May 2020.
The European Union’s new Medical Device Regulations (EU MDR) will require that all medical devices – even legacy products – have updated clinical data and technical documentation to support device safety and conformity with the new regulatory standards, Sandi Schaible tells MD+DI. Schaible is the senior director of analytical chemistry at WuXi AppTec, where she specializes in extractables and leachables studies. She is a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization. She is also a U.S. delegate for ISO 10993 part 13 and the particulates committee.
MD+DI asked Schaible a few questions about what medical device manufacturers can expect with the new requirements and what steps they can take now to prepare.
What do medical device manufacturers need to know about how the EU MDR will change requirements for medical device testing and data documentation, both pre and post CE marking?
Schaible: MDR requires that you provide robust data to demonstrate the performance and safety of your device. Regulators will be looking to see that the device has been challenged under harsh conditions and that all chemical, toxicological, and biocompatibility information has been accounted for. The new standards will place more emphasis on the importance of chemistry. Be sure that no unknown substances surface in your chemistry reports, and in the case that unknowns do appear, you should be prepared to repeat your testing or provide supplemental information.
If your device is a Class I reusable device (Class Ir), a notified body must review the device’s technical file to confirm compliance before you can obtain a new CE mark. The technical file should prove the safety and efficacy of the cleaning, disinfection, and sterilization processes outlined in the device’s Instructions for Use (IFUs). While OEMs have been permitted to self-designate their devices as Class Ir in the past, this will not be the case under MDR. Additionally, Class Ir devices cannot be grandfathered in or receive extensions, so prioritizing these devices is prudent.
What are the risks to a medical device manufacturer’s product portfolio?
Schaible: The risks of unpreparedness are vast. Failure to act with urgency could lead to time-consuming regulatory delays, additional costs, wasted resources, or, worst of all, having a device pulled from the EU market. Since both new and legacy products will require updated technical data, millions of devices need to be reviewed in a short amount of time. If your submission is not bulletproof before it reaches regulators the first time around, you may have to perform additional testing before you can get back in line, jeopardizing your device and revenue streams.
How is testing changing, how will consensus standards help, and what should medical device manufacturers ask of standards bodies, notified bodies, and supplier partners?
Schaible: Performing complete biological evaluations will be of greater importance under MDR. For this reason, all medical devices must address three sequential stages of preclinical safety testing – chemical characterization, toxicological risk assessment, and biocompatibility evaluations. Another important factor to take into consideration is the reclassification of devices under MDR. For example, devices that were previously considered accessories may now fall into a whole new device category, such as Class Ir. Knowing what class your device falls into is important when it comes to planning and prioritization during the gap analysis and pre-clinical testing stages.
As testing changes, consensus standards create more consistent and updated benchmarks for the global marketplace of medical devices. New changes, like those to ISO 11607 Parts 1 and 2, aim to harmonize terminology and facilitate a mutual understanding of expectations. This is especially important in emerging marketplaces, as it brings medical devices onto a level playing field.
Working with various stakeholders like standard bodies, notified bodies, and other partners can get complicated, but asking the right questions will help kick off conversations in the right direction. Here are some key questions to ask:
- CRO or laboratory testing partner: Does your laboratory conduct chemical characterization, toxicological risk assessments, and biocompatibility testing in-house? Enlisting a partner that has all three capabilities in-house increases efficiency, allows you to address required endpoints, and helps eliminate information gaps. If you have to piecemeal testing, it can cause longer timelines, increased cost, miscommunication between parties, loss of information altogether, and unknown impurities getting missed in your chemical reports.
- CRO or laboratory testing partner: How do you perform E/L studies for complete identification? Changes to the ISO 10993 standard will require the identification of compounds about the analytical evaluation threshold (AET). If the laboratory you’re working with reports unknowns, you can run into problems with your risk assessment and ultimately your submission. If regulators reject your submission or issue requests for additional information, you may be required to re-test the device.
- CRO or laboratory testing partner: Do your analytical methods provide enough sensitivity for the toxicological risk assessment? Analytical test methods that are not sensitive enough to detect chemicals above the analytical evaluation threshold may lead to challenges for the toxicologist writing the risk assessment and ultimately your submission. Make sure the testing laboratory and toxicologist are on the same page regarding instrument sensitivity/reporting limits.
- CRO or laboratory testing partner: Do you provide support after a submission is complete? Follow-up support on testing is important in the event that regulators pose questions or request supplemental information.
- Standards bodies: How can OEMs and testing laboratories remain active in the conversation around new regulations? Being proactive on upcoming changes will allow you to manage potential risks associated with your device and influence the conversation to consider your perspective and capabilities. These influences can benefit the entire community by ensuring relevant terminology is put in place and timing of regulations is feasible.
- Notified bodies: What collaborative efforts are most important from an OEM and testing laboratory? Cultivating positive relationships with notified bodies can create trust and build communication proficiencies that benefit overall compliance.
You mention performing a gap analysis. Can you explain what that would entail, who performs it, and what action plan could be put in place?
Schaible: A gap analysis is an evaluation that OEMs can use to identify missing information in pre-existing data and product portfolios. This step can take up to a few months to complete, but making this time investment at the forefront can mitigate the risk of running into additional regulatory hurdles down the road. It’s best practice to complete a gap analysis before developing a pre-clinical testing strategy. The process should involve a team of cross-functional experts from quality, project management, and engineering departments. If outsourcing your gap analysis, look to a consultant or an expert toxicologist that can demonstrate the expertise and capabilities necessary to accurately identify missing information, prioritize products, and build a robust test plan.
Questions to consider:
- What is the age of your device? Older devices that have not undergone testing since they were originally manufactured may require more legwork. Their technical files may contain information that is insufficient under the new standards and therefore should be prioritized accordingly. There have been several updates to standards in the past few years and expectations of regulatory bodies have changed as well. For example, testing conducted only three years ago may no longer be sufficient under today’s expectations.
- Have any changes been made to the device since it was last tested? In order to be considered ‘up-to-date’ data, all changes, even those that are minor, must be appropriately documented. Device changes could impact chemical make-up or potential risk outcomes, and regulators will be looking for data that supports the safety of all individual material components, chemical constituents and mechanical processes used on and within the device.
- Have any patient safety issues been reported in association with the device? If you answered “yes,” you will undoubtedly need to pursue testing. This will be your opportunity to show regulators that corrective actions have been taken to rectify gaps.
Action plans to perform a gap analysis will vary by product and company, however, educating internal teams on regulatory changes, organizing technical files early on, properly vetting partners, and approaching partnerships with transparency will get you started down the right path. Get going on your gap analysis now to save time and money in your submission process.
What are some gap analysis missteps to be aware of?
Schaible: First, you should know that providing a testing partner outdated or incomplete information can negatively impact their research process. It is important to provide them with the original information in one comprehensive technical file to give them the whole picture and allow them to make informed decisions on what tests need to performed to fully support the device’s safety. The more transparent you are, the better. Second, citing old research that no longer meets quality standards of new regulation will result in a failed submission. The gap analysis is the stage at which holes in existing information are identified, so skipping this step is detrimental to your entire data package. Maintaining a proactive relationship with regulatory bodies is important in avoiding misunderstanding of current regulations or citation of outdated regulations. Finally, neglecting to present a detailed history of any changes made to the device since it was last reviewed by regulators will severely impact submission accuracy. Seemingly minor details like this could be easily overlooked without a gap analysis; however, the consequences may be catastrophic.
How can a company get started?
Schaible: Rounding up a group of the right people and resources is the first step in preparing for MDR. With a cross-functional team that is informed on the changes and business impacts of new regulation, and a planful approach your organization can ensure that devices achieve regulatory approval before deadlines go into effect. As you begin the planning process, your internal team should start collecting existing data on the materials that make up your devices, as well as procedures used in manufacturing and sterilization. This information will aid you in the planning process to ensure safety is upheld and technical files demonstrate compliance with new standards.
What are the pitfalls and how can they be avoided?
Schaible: Many of the pitfalls in preparing for MDR stem from the same seed – unpreparedness. Procrastination and disorganization will undoubtedly lead to rushed and incomplete processes and teams. OEMs must define a planning process and establish partnerships early on to avoid running into costly, time-consuming regulatory hurdles. Communicate early and often to mitigate the risk of overlooking gaps in data, educate key players on the changing regulatory landscape, and establish partnerships to develop a bulletproof pre-clinical testing strategy. On average, repeat testing can cost more than $75,000 and 27 weeks of time, so it is important to do things right the first time around and to remain systematic from start to finish.
Manufacturers of Class I reusable (Class Ir) medical devices need to identify data gaps and select the appropriate validation study to ensure their devices’ compliance with the European Commission’s Medical Device Regulation (MDR).
The introduction of MDR is putting increased emphasis on the roles that robust data and complete evaluations play in ensuring medical device safety. All devices, including Class I reusable devices (Class Ir), must meet the new guidelines or risk being excluded from the market.
Class Ir devices are designed to be used more than once and across patients. To obtain a CE Mark under MDR, these devices will require a detailed technical file that proves safety and efficacy of cleaning, disinfection and sterilization methods outlined in the device’s Instructions for Use (IFU). Historically, Class I devices, including reusable products, were self-designated, leaving it up to device manufacturers to decide what a validation entailed. But under MDR, every device manufacturer will be responsible for ensuring cleaning, disinfection and sterilization instructions are adequate and validated. A notified body will review the technical files, including these validations, to confirm they comply with MDR and are acceptable according to international standards and industry guidance.
As the May 26, 2020 deadline draws near, it is important to note that reusable devices won’t have the luxury of receiving an extension or being grandfathered in. Therefore, prioritize them early, starting by conducting a gap analysis and appropriate validation studies.
Conduct a gap analysis
Before investing time and money on testing, perform a gap analysis to determine where deficiencies exist in your data and product portfolios. Notified bodies will not rely on historic product performance or reviews alone.
Start by reviewing the technical files for your current Class Ir devices to identify missing information or outdated test strategies. This is especially important for MDR compliance, as you will need to confirm that validations exist in the design file that support instructions for use (IFU) claims and meet current ISO standards, including ISO 17664:2017.
Begin with legacy devices, as those have been on the market longer and will likely take more time. If a product family consists of multiple catalog numbers and SKUs, you must document validation evidence across all of the devices.
Prepare for testing
If the analysis identifies data gaps, run a validation test to rectify them and gather new data or supplemental information. This process can be laborious, but working with a contract research organization (CRO) or laboratory testing partner may help. They can identify and perform appropriate tests to ensure compliance. It is also helpful to identify a partner that can develop experimental design and validation methods that are compliant with the latest guidance and regulatory documents.
If validation testing is required, start by identifying the type of study or studies needed for your product or product family. Then, validation protocols are developed and customized to your product, its IFU and worst-case conditions. Here are some examples of the studies that may be needed:
- A cleaning efficacy study validates the efficacy of your recommended cleaning process. It requires that you test devices with clinically relevant artificial soils and other worst-case parameters that confirm the process is reliable and repeatable and ensures that clean endpoints are met.
- Sterilization efficacy studies are used to verify that the sterilization methods successfully achieve a targeted sterility assurance level (SAL), even in worst-case scenarios.
- Dry time validations studies are needed because healthcare facilities must know the effective dry time for devices sterilized using steam. It will be important to have data to back that the drying cycle works according to the given parameters.
- Support functionality studies by exposing devices to multiple cleaning, disinfection and/or sterilization cycles beforehand.
- Disinfection efficacy studies will produce documentation showing that selected disinfectants can reduce microorganisms to acceptable levels on the medical device. It is important to note that a cleaning validation and its construct is separate from a disinfection validation. Independent protocols and reports for each must be generated to document the effectiveness of each reprocessing step.
Because these studies can be costly and time-consuming, it is important to perform them properly the first time. Make sure to do the following when conducting your studies:
- Select clinically relevant test soil
- Simulate worst-case conditions
- Include proper test controls
- Use two or more cleaning endpoint markers
- Include accumulation cycles
- Perform recovery efficiency
- Perform validations independently
- Demonstrate and document appropriate test soil drying times
After testing is complete, you will need to submit your data to a notified body. However, under MDR, every notified body will have to go through a new designation and notification process before it will be eligible to review your device’s technical file and approve a CE Mark. Communicate with your notified body early and get your device in line, as the industry anticipates capacity constraints.